tbuckley/cabot-search huggingface dataset:
LGG-15. Late mortality and morbidity of adult survivors of childhood glioma treated across three decades: a report from the Childhood Cancer Survivor Study
Authors: Peter M K de Blank, Katharine R Lange, Mengqi Xing, Sedigheh Mirzaei Salehabadi, Deokumar Srivatava, Tara M Brinkman, Kirsten K Ness, Kevin C Oeffinger, Joseph Neglia, Kevin R Krull, Yutaka Yasui, Paul Nathan, Rebecca Howell, Lucie Turcotte, Wendy Leisenring, Gregory T Armstrong, Daniel C Bowers, M Fatih Okcu
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Pediatric low-grade glioma therapy has evolved to delay or eliminate radiation. The impact of therapy changes on long-term outcomes remains unknown. METHODS: Cumulative incidence of late mortality (death &amp;gt;5 years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions (CHCs, CTCAE grading criteria) were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of glioma diagnosed 1970-1999. Outcomes were evaluated by diagnosis decade and by treatment exposures received ≤5 years following diagnosis (surgery-only, chemotherapy ± surgery, and cranial radiation ± surgery or chemotherapy). Relative risk (RRs) with 95%CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS: Among 2,684 eligible survivors (age at diagnosis (median [range]), 7 years [0-20 years]; time from diagnosis, 24 years [5-48 years]), exposure to cranial radiation decreased [51% (1970s), 45% (1980s), 25% (1990s)] along with late tumor recurrence (&amp;gt;5 &amp; ≤15 years from diagnosis) [9.8% (1970s), 8.8% (1980s), 5.0% (1990s)]. The 15-year cumulative incidence of late mortality was 10.3% (1970s), 6.5% (1980s), and 6.0% (1990s) (p&amp;lt;0.001, comparison of cumulative incidence curves). The 15-year cumulative incidence of grade 3-5 CHCs was 19.7% (1970s), 17.8% (1980s), and 14.2% (1990s) (p&amp;lt;0.0001). A reduction in SN incidence was not observed. In multivariable analyses excluding treatment exposure, later diagnosis (1990s vs. 1970s) was associated with lower risk of late mortality, grade 3-5 CHCs and SNs. Inclusion of treatment exposure in the model attenuated the effect of diagnosis decade. Radiation or chemotherapy exposure increased risk compared to surgery alone for late mortality (radiation RR 4.95, 95%CI 3.79-6.47; chemotherapy RR 2.88, 95%CI 1.85-4.48), CHCs (radiation RR 4.02, 95%CI 3.28-4.94; chemotherapy RR 1.66, 95%CI 1.13-2.45), and SNs (radiation RR 4.02, 95%CI 3.06-6.13, chemotherapy RR 2.08, 95%CI 1.03-4.23)). CONCLUSION: Late mortality and CHCs decreased in childhood glioma survivors diagnosed from 1970-1999 largely due to therapy changes, particularly avoidance of cranial radiation, without increased late recurrence.
Is ECOG-PS ≥3 appropriate to guide rehabilitation referral decisions? Using patient-reported outcome measures to examine the prevalence of functional disability in patients with ECOG-PS 0-2.
Authors: Kelley C Wood, Mary Hidde, Tiffany Kendig, Ellen A. Ronnen, Rachel Carroll, Smith Giri, Grant Richard Williams, Mackenzi Pergolotti
Journal: Journal of Clinical Oncology (2022)

e18724 Background: Outpatient physical or occupational therapy (PT/OT) can optimize cancer patients’ performance status and ability to complete instrumental activities of daily living (IADL). The American College of Sports Medicine recommends referral to PT/OT for those with Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥3/5. However, ECOG-PS alone may not accurately indicate needs for PT/OT. We used functional patient reported outcome measures (F-PROM) to quantify the prevalence of functional disability for cancer patients with favorable ECOG-PS (0-2) starting a new line of systemic therapy. Methods: Patients with cancer at a multi-office community-based oncology private practice who were enrolled in a clinical trial (NCT04852575) completed a validated online geriatric assessment (the Cancer Aging Resiliency Evaluation) including F-PROM before starting a new line of systemic treatment. F-PROM included: Patient Reported Outcome Measurement System (PROMIS) - Cognitive Function (4 item, T-score = 41-80); impact of physical/emotional problems on social activities (social impact, 1-item); ability to walk one block (1-item); pain (0-10); and ability to perform nine IADL (3-point Likert scale). We extracted clinical characteristics from medical records, then used descriptive statistics and established F-PROM disability cut off to quantify the prevalence of functional disability. Results: Most patients (N = 86) were female (58%) and diagnosed with stage 3 or 4 (68%) breast (33%) or gastrointestinal cancer (24%). The mean±SD age was 64.3±10.7 years. ECOG was 0 (66%) or 1 (34%); none had ECOG-PS of &gt;2. Across F-PROM, prevalence of disability ranged 24% (cognitive function) to 42% (social impact), see Table. IADL disability was reported by 31% of patients; median number of unique IADL disabilities was 3 (IQR = 1-4). Most common IADL disabilities were housework (29%), shopping (19%), ability to get to places out of walking distance (16%), and meal preparation (14%). Conclusions: Despite favorable ECOG-PS (0-1), 24 to 41% of patients starting a new line of systemic therapy in this study had one or more needs amendable to PT/OT. Future work should identify strategies to integrate F-PROM into routine oncology practice to identify rehabilitation needs and evaluate if subsequent PT/OT improves patient outcomes. Clinical trial information: NCT04852575. [Table: see text]
Outcomes of neoadjuvant combination chemotherapy with and without targeted therapy in HER2-positive breast cancer: A real-world experience from tertiary care center in North India.
Authors: Anshul Gupta, Ajay Gogia, Hari Krishna Raju Sagiraju, S.V.S. Deo, Dayanand Sharma, Sandeep Mathur, Ritu Gupta
Journal: Journal of Clinical Oncology (2022)

e12601 Background: Neoadjuvant chemotherapy (NACT) with HER2 blockade is preferred approach for treatment of early and locally advanced HER2 positive breast cancer. However, there is a lack of survival data with respect to pathological complete response (pCR) from India. Methods: We retrospectively evaluated 211 HER2 positive female breast cancer patients registered between years 2014 and 2021, who received three different NACT regimens (i) Anthracycline free TCH (n=116) [docetaxel (75mg/m 2 ), carboplatin (AUC = 6) and trastuzumab (8mg/kg loading followed by 6mg/kg) with G-CSF q 21 days], (ii) EC-TH (n=52) [epirubicin (90 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ) for 4 cycles followed by 4 cycles of docetaxel (85mg/m 2 )] and (iii) EC-T (n=43, without trastuzumab due to financial constraints). Primary end point was pCR. Secondary end points were disease free survival (DFS), Overall Survival (OS) and safety profile. Results: Median age was 45 years (24-71), 88 (41.7%) were postmenopausal and 104 (49.3%) were ER/PR positive. Twenty-two (10.4%) patients were stage II, 164 (77.7.%) were stage III and 25 (11.9%) were oligometastatic stage IV. Distribution of age, performance status, tumor size and nodal positivity were comparable across the study groups. Pathological CR in trastuzumab containing groups, was higher compared to non-trastuzumab containing group (35.8% vs 20%, p=0.045) and was similar between, TCH and EC-TH groups. Median follow-up was 32.9 months (5.7-108), 3-year DFS and OS were 54.8% and 92.1% respectively. Pathological CR rates and survival outcomes of the three groups are given in table 1. When stratified by pCR status, in the trastuzumab containing groups, achievement of pCR translated to improved DFS (log rank p=0.01). This survival advantage of pCR was not seen in non-trastuzumab containing group. The outcome of trastuzumab containing both regimens were similar. Grade 3/4 toxicities were recorded in 21.6% of TCH, 26.7% of EC-TH and in 25.2% of EC-T groups. Most common toxicities were anemia (16.3%), thrombocytopenia (14.2%) and vomiting (10.2%). Conclusions: Trastuzumab containing regimens impact pCR rates and in turn the survival outcomes among Indian women with HER2 positive breast cancer. Safety and efficacy of anthracycline free TCH regimen is comparable with EC-TH.[Table: see text]
Non-muscle invasive bladder cancer subtypes with differential response to intravesical bacillus Calmette-Guerin treatment
Authors: F.C. De Jong, T.D. Laajala, R.F. Hoedemaeker, S. Rinaldetti, K. Jordan, A.C.J. Van Der Made, B. Nieuwkamer, E.R. Boevé, E.A.M. Janssen, T. Mahmoudi, J.L. Boormans, D. Theodorescu, J.C. Costello, T.C.M. Zuiverloon
Journal: European Urology (2022)
Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma
Authors: Paola Ghione, M. Lia Palomba, Anik R. Patel, Sabela Bobillo, Kevin Deighton, Caron A. Jacobson, Myrna Nahas, Anthony J. Hatswell, A. Scott Jung, Steve Kanters, Julia Thornton Snider, Sattva S. Neelapu, Maria Teresa Ribeiro, M. Alan Brookhart, Herve Ghesquieres, John Radford, John G. Gribben
Journal: Blood (2022)

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.
Impact of histopathological revision and molecular pathology in the diagnosis of sarcomas in a reference center in Brazil.
Authors: Carlos Diego Holanda Lopes, Marcello Moro Queiroz, Luana Alencar Fernandes Sampaio, Andre Perina, Eduardo Hiroshi Akaishi, Frederico Ribeiro Teixeira, Fabio Oliveira Ferreira, Samir Abdallah Hanna, Joao Luis da Silva, Luiz Guilherme C. A. De Lima, Claudia Regina G. C. M. De Oliveira, Rodrigo Ramella Munhoz
Journal: Journal of Clinical Oncology (2022)

e23533 Background: The accurate classification of sarcomas remains a major challenge due to the diversity and rarity of this group of mesenchymal tumors. In addition to standard microscopy and immunohistochemical techniques, molecular analyses are often required to achieve an appropriate diagnosis. The limited availability of specialized pathology centers, multidisciplinary teams, and diagnostic tools may directly affect the initial evaluation and subsequent treatment plan. Therefore, we sought to characterize the impact of diagnostic review by reference pathologists and molecular assessments in a reference center in Brazil. Methods: We conducted a retrospective analysis of sarcoma samples initially analyzed at outside laboratories and subsequently revised in a reference center by two dedicated pathologists between 01/2014-12/2020. After extracting demographic and tumor characteristics, we assessed the presence of complete discordance (benign versus malignant, sarcoma versus other malignancy), partial concordance (similar diagnosis of connective tumor, but different grade/histological subtype/differentiation), and complete concordance. The concordance for histology or grade, as well as the role of molecular assessments supporting the diagnosis, were also independently determined. Statistical analyses were conducted through the kappa coefficient of agreement, adherence by χ2 test, χ2 test by Person, and Fisher's exact test. Results: A total of 197 cases were included, with a predominance of male patients (57.9%), localized tumors (86.8%), and the median age at diagnosis of 46.3 years. The most common primary sites were lower extremities (34.6%) and retroperitoneum (11.3%). Following the revision, the most frequent histologies were undifferentiated pleomorphic sarcoma (20.3%), liposarcomas (13.1%), and leiomyosarcoma (6.6%). Complete discordance was present in 13.2%, partial discordance in 45.2%, and complete concordance in 41.6% of reviews (p &lt; 0.001). We found a concordance for histology or grade of 53.5% (p &lt; 0.001) and 51.8% (p &lt; 0.001) respectively. Molecular assessments, comprising NGS panels (79.5%) and FISH (20.5%), were performed in 44 (22.3%) cases, with findings of diagnostic relevance in 31.8% of those. Conclusions: In almost 60% of the cases, the initial diagnosis was at least partially modified when revised in a reference center, with a relevant impact of molecular assessments. These findings highlight the importance of managing sarcoma patients in reference centers and justify the assembly of referral networks in countries with limited healthcare resources.
Literature on target therapy of malignant melanoma.
Authors: Mohammad Ali Esmaeil Pour, Mahsa Mohebtash, Ali Amin, Azadeh Khayyat, Amir-Reza Khalili-Toosi, Mengni Guo, Seyedreza Mousavi, Jieying Liu
Journal: Journal of Clinical Oncology (2022)

e21506 Background: Malignant melanoma (MM) of mucosal membranes (excluding anus and head and neck) is a rare but aggressive disease with poor outcome. There is little information available on the mechanism of development, risk factors and management of this tumor, mainly due to the low number of cases. Methods: We performed a literature review on MMM (between 1970-2020) with a focus on nonsurgical management and outcome. Results: We identified 9-papers discussing 1500-MM cases. Formerly, for the management of MMM, Dacarbazine, Interferon b, DAV-Feron, Carboplatin, Imatinib, and Paclitaxel were administered. More recently, novel immunotherapeutic and chemotherapeutic medications such as Immune Checkpoint Inhibitors (ICPI) and anti-VEGF agents have been administered in these patients. In 502 patients of metastatic MMM, adding ipilimumab to dacarbazine increased OS from 9.1-to-11.2 months with one year survival increasing from 36.3%-to-47.3 %. For nivolumab &amp; ipilimumab combination therapy in 361 patients with MMM and CMM, MPSF in nivolumab monotherapy was 3-months and 6.2-months (for MMM and CMM, respectively); but in nivo-ipili combination, MPFS was 5.9-months and 11.7-months (for MMM and CMM, respectively). A benefit of bevacizumab addition to platinum-based chemotherapy in patients showing advanced disease on ICPI is unknown; however, combination-therapy may be reasonable if no access to ICPI or autoimmune diseases. Conclusions: MMM patients could benefit from combination of nivolumab to ipilimumab more than monotherapy with either medication alone.[Table: see text]
Value of adjuvant radiotherapy in patients with localized Ewing sarcoma at the extremities: Report from the Ewing 2008 trial.
Authors: Philip Heesen, Andreas Ranft, Vivek Bhadri, Bénédicte Brichard, Stephane Collaud, Sona Cyprova, Hans-Theodor Eich, Torben Ek, Hans Gelderblom, Lianne Havemann, Peter Hauser, Heribert Juergens, Jukka Kanerva, Thomas Kuehne, Anna Raciborska, Jelena Rascon, Arne Streitbuerger, Beate Timmermann, Yasmine Uhlenbruch, Uta Dirksen
Journal: Journal of Clinical Oncology (2022)

11531 Background: In patients with Ewing Sarcoma (EWS), adjuvant radiotherapy is often performed after surgery that could not obtain wide margins or after poor histological response to surgery. However, the benefit of adjuvant radiotherapy needs further investigation. Therefore, we compared event-free survival (EFS) between surgery (SX) alone and SX combined with radiation therapy (RT), performed a subgroup analysis and identified independent prognostic factors. Methods: The data from localized EWS patients with tumors at the extremities that were treated in the Ewing 2008 trial from 2009-2018 were included in this analysis. Patients received induction chemotherapy according to the protocol and then underwent local therapy. Patients receiving SX or adjuvant RT (combined SX/RT) were included in this analysis. Hazard ratios (HRs) (95% Confidence Intervals (CIs)) were calculated using Cox regression. Results: 360 out of 863 patients (41.7%) presented with an EWS at the extremities with 81 tumors at the upper extremity, and 279 tumors at the lower extremity. Most patients were treated with surgery only (223, 61.94%), while 125 patients (34.72%) were treated with SX plus RT. Adjuvant radiotherapy was conducted after a median time of 69 days (1 st quartile, 3 rd quartile; 54, 109). Median EFS at 5-years for all patients was 0.74 (0.69, 0.80), 0.76 (0.70, 0.83) for patients after surgery only, and 0.73 (0.64, 0.83) after combined RT/SX. After adjusting for sex, age, tumor volume, histological response and surgical margins, the HR for combined RT/SX vs SX alone was 0.69 (0.37, 1.26), p = 0.22. In patients with poor histological response to surgery (≥10% vital tumor cells) and with high tumor volume (≥ 200mL), additional radiotherapy did not decrease the hazards of any event, HR 0.72 (0.25, 2.06), p = 0.54. We identified high tumor volume, poor histological response to surgery as well as intralesional resection of the tumor as independent prognostic factors after adjusting for other known prognostic factors with HRs of 1.73 (1.04, 2.90), p = 0.03; 2.79 (1.69, 4.62), p &lt; 0.0001 and 215.9 (13.17, 3538.61), p = 0.0002, respectively. Surgical complication was not a prognostic factor after adjusting for above mentioned variables, HR 0.85 (0.31, 2.34), p = 0.75. Conclusions: In our cohort, adjuvant radiotherapy was not superior compared to surgery alone in all patients with localized EWS at the extremities and neither in a subgroup of patients with high-risk factors. Poor histological response, intralesional tumor resection as well as high tumor volume were identified as independent negative prognostic factors. Clinical trial information: NCT00987636.
Clinical activity of pembrolizumab monotherapy in diffuse malignant peritoneal mesothelioma.
Authors: Xiao Wang, Michael Offin, Leonid Roshkovan, John Miura, Michelle S. Ginsberg, Christine Agnes Ciunci, Jacklynn V. Egger, Suzanne Walker, Andrea Cercek, Leslie Litzky, Garrett Michael Nash, Andrew Haas, Giorgos Karakousis, Keith A. Cengel, Sharyn I. Katz, Marjorie Glass Zauderer, Corey J. Langer, Melina Elpi Marmarelis
Journal: Journal of Clinical Oncology (2022)

8557 Background: Among patients with malignant mesothelioma, pembrolizumab has demonstrated activity in diffuse pleural mesothelioma (DPM), with limited data available for those with diffuse malignant peritoneal mesothelioma (DMPM). DMPM represents a clinically distinct entity from DPM and disease specific outcomes data is needed. We present real world data on the efficacy of pembrolizumab in DMPM. Methods: In this retrospective study, we identified patients with DMPM treated with pembrolizumab at two tertiary care cancer centers between 1/1/2009 and 1/1/2021. Clinicopathologic features were annotated. Median progression free survival (mPFS) and median overall survival (mOS) were calculated using Kaplan-Meier curves. Best overall response rate (BOR) was determined using RECIST 1.1 criteria. Association of partial response with disease characteristics was evaluated using Fisher’s exact test. Results: We identified 24 patients with DMPM who received pembrolizumab (median age 62 years, 63% never smokers, 58% female, 75% had epithelioid histology). All patients received systemic chemotherapy prior to pembrolizumab (median prior lines of therapy: 3). BOR was 17% (3 partial responses, 10 stable disease, 5 progressive disease, 6 lost to follow-up). With a median follow up time of 29.2 months, mPFS was 4.9 months and mOS 20.9 months from pembrolizumab initiation. Three patients experienced PFS of &gt; 2 years. Among the 14 patients who underwent next generation sequencing of tumor tissue, there were 8 somatic BAP1 alterations. Among the 17 patients tested for PDL1, 6 had positive PDL1 expression (1-80%). There was no association between partial response and presence of a BAP1 somatic alteration (p = 0.453), PDL1 positivity (p = 0.7) or non-epithelioid histology (p = 0.55). Conclusions: Pembrolizumab is active in a PDL1 unselected cohort of patients with DMPM. The overall response rate of 17% and mPFS of 4.9 months in this 75% epithelioid histology cohort warrants further investigation to identify those most likely to respond to immunotherapy, especially among epithelioid histology.
EPEN-26. Chemokine receptor blockade reverses CCL2 mediated immunosuppression and restores CAR-T cell function in posterior fossa ependymoma
Authors: Allison P Cole, Andrew M Donson, Angela M Pierce, Enrique Grimaldo, Jacob D Calhoun, Andrea M Griesinger, Caroline Sublett, Rosandra N Kaplan, Terry J Fry, Nicholas K Foreman, Anandani Nellan
Journal: Neuro-Oncology (2022)

Abstract Trastuzumab-based HER2 CAR-T constructs have demonstrated preclinical efficacy in medulloblastoma and are being evaluated for use in children and young adults with recurrent or refractory CNS tumors. Preliminary results demonstrate immune activation but no objective tumor response in three patients, including two patients with posterior fossa (PF)-EPN. A key finding in the serum and CSF of all three patients was very high levels of the inflammatory chemokine CCL2 following treatment with CAR-T cells. Preclinical studies suggest that high levels of CCL2 may impede T cell mediated anti-tumor activity in CNS tumors. The role of CCL2 to enhance or diminish CAR-T cell efficacy for CNS tumors is unknown. We evaluated a second generation trastuzumab-based HER2 CAR construct with a 4-1BB co-stimulatory domain in two ultra-high-risk patient-derived xenograft (PDX) models that faithfully recapitulate PFA-EPN. In contrast to preclinical studies in other cancers, treatment with trastuzumab-based HER2 CAR-T cell alone causes only partial regression of tumors and robust infiltration of immunosuppressive monocytes in PFA-EPN PDX mouse models. We studied constitutive NF-kB activation because it is a hallmark of PFA-EPN that drives dysregulation of inflammatory genes and forms an immunosuppressive tumor microenvironment. Upon tumor recognition, CAR-T cells produce high amounts of the cytokine tumor necrosis factor-alpha, which is an extracellular stimulus that propagates NF-kB activation in PFA-EPN. We show that HER2 CAR-T cell treatment causes increased nuclear translocation of the RELA NF-kB subunit, which induces CCL2 gene transcription and chemokine release. This results in CCL2-CCR2 ligand/receptor mediated influx of inflammatory monocytes and regulatory T cells, impairing CAR-T cell effector function. Inhibition of CCR2 restores anti-tumor CAR-T cytotoxicity against bulky orthotopic tumors by decreasing the infiltration of inflammatory monocytes and regulatory T cells. Combinatorial strategies addressing tumor mediated immunosuppression should be evaluated in upcoming CAR-T cell trials for patients with high-risk CNS tumors.